Benzohydroxamic acid derivatives



United States Patent U.S. Cl. 260500.5 8 Claims ABSTRACT OF THEDISCLOSURE Compounds of the formula wherein R is hydrogen, lower alkylor phenyl-lower alkyl, R is hydrogen or lower alkyl, R is lower alkyl orlower alkenyl, R is nitro, amino, lower alkylamino or di-loweralkylamino and A is oxygen or sulfur, are useful in coc cidiostatcompositions.

This application is a division of application Ser. No. 550,948, filedMay 18, 1966.

Coccidiosis is a disease affecting primarily poultry and is caused byprotozoa of the genus Eimeria, especially E. tenella, E. necatrix and E.acervulina. This disease causes severe and frequently fatal infection inpoultry flocks. It constitutes a serious economic hazard.

Current practice in poultry raising is the feeding of coccidiostaticpreparations in the general diet as a prophylactic measure. Knowncoccidiostats have failings in that they are not as highly effective asdesirable, do not exert their effect against all species of infectiveorganisms, are not free of undesirable side effects and/or are noteconomically feasible. It is an object of this invention to providecompounds and compositions which prevent the development and spread ofcoccidosis effectively at low, economical levels and also foradministration in treatment of the disease.

Although the compounds of this invention are preferred for use againstcoccidiosis, they also have antimicrobial activity, for example, incombating Staphylococcus aureus, Trichomonas vaginalis or Escherischiacoli.

The compounds of this invention have the formula I 0R 0 II I wherein Ris hydrogen, lower alkyl or phenyl-lower alkyl, e.g., benzyl, R} ishydrogen or lower alkyl, R is lower alkyl or lower alkenyl, R is nitro,amino, lower alkylamino or di-lower alkylamino and A is oxygen orsulfur.

The lower alkenyl groups in all of the substituents referred to aboveare straight or branched chain hydrocarbon groups such as methyl, ethyl,propyl, isopropyl, butyl, s-butyl, t-butyl and the like. The loweralkenyl groups are of the same type including a double bond. In eachinstance, methyl is the preferred lower alkyl group. The preferredcompounds of Formula I are those wherein R and R each is hydrogen, A isoxygen or sulfur, R is methyl or ethyl and R is nitro.

Illustrative compounds include 2-methoxy-4-nitrobenzohydroxamic acid,2-ethoxy-4-nitrobenzohydroxamic acid,2-ethylmercapto-4-nitrobenzohydroxamic acid, 2-ethoxy-4-dimethylaminobenzohydroxamic acid,O-methyl-Z-ethoxy-4-nitrobenzohydroxamic, acid, N-methyl-2-ethoxy-4-3,474,132 Patented Oct. 21, 1969 2 nitrobenzohydroxamic acid,N,O-dimethy1-2-ethoxy-4- nitrobenzohydroxamic acid,O-benzyl-2-ethoxy-4-nitrobenzohydroxamic acid,2-allyloxy-4-nitrobenzohydroxamie acid and the like.

The compounds of Formula I may be synthesized by the reaction of an acylhalide of the formula in wherein Z is halide, preferably chlorine orbromine,

R is nitro, diloweralkylamino, with an hydroxylamine of the formula(III) 1 I INOR wherein R and R are as previously defined.

Those compounds wherein R is amino are obtained by the reduction of thecorresponding compound in which R is nitro.

Alternatively, the compounds of Formula I may be synthesized by thereaction of a. lower alkyl ester, preferably the methyl ester of an acidof the formula lH-Q-O-lower alkyl with an hydroxylamine.

The compounds of Formula I and especially 2-ethoxy-4-nitrobenzohydroxamic acid, are most effectively provided to the animalin its food or drink. Thus it may be placed in solution or in suspensionin its drinking water or preferably admixed in the feed composition.

The compositions of this invention may be produced by intimatelydispersing the active coccidiostatic ingredient throughout a carrier ordiluent which is either solid or liquid. Preferably, the compound isthoroughly admixed with a major proportion of poultry feed supplied tothe fowl, e.g., chick starter, broiler and grower feeds, laying mashes,breeder and turkey breeder mashes, turkey starter and grower feeds andthe like.

The active material may also be incorporated in premixes wherein higherproportions of the active ingredients are present. The concentratedpremix is then diluted with additional feed by the feed supplier orpoultry grower, for example, one pound of premix per ton of feed, toobtain a feed containing the requisite amount of coccidiostat.

It will also be appreciated that the active ingredients may be suppliedin combination with an inert carrier or diluent such as Attapulgus clay,bentonite or edible vegetable materials. Liquid dispersions in water canbe prepared by using emulsifiers and/or surface active agents.

The amount of compound of Formula I incorporated in the food or water isthe range of about 0.005 to 0.5% (by weight), preferably about 0.02 to0.04%. In addition, the incorporation of a tetraalkylthiuram disulfide,e.g., tetramethylthiuram disulfide, tetraethylthiuram disulfide and thelike, frequently enhance the action of a compound of Formula I and thusconserve the amount of the latter required. Thus, a total of about 0.005to 0.1% (by weight) preferably about 0.01 to 0.03% of the combinedsubstances in the feed is usually adequate. Approximately equalproportions (percent by weight) of the two components are sufficient,but a ratio of about 1 to 3 of the hydroxamic acid to about 1 to 3 partsof the disulfide may be used. The preferred combination containsZ-methylmercapto-4-nitrobenzohydroxamic acid and tetraethylthiuramdisulfide.

The following examples are illustrative of the invention. Alltemperatures are on the centirgrade scale.

EXAMPLE 1 2-ethoxy-4-nitrobenzohydroxamic acid (a)2-ethoxy-4-nitrobenzoyl chlride.A mixture of grams of2-ethoxy-4-nitrobenzoic acid and ml. of thionyl chloride is refluxed forthree hours and then concentrated under reduced pressure to remove theexcess thionyl chloride. Twenty milliliters of anhydrous hexane is thenadded to the residue and the solvent removed by distillation to removethe last traces of the thionyl chloride. The residue of2-ethoxy-4-nitrobenzoyl chloride is used without further purification.

(b) Z-etlz0xy-4-nitr0benzohydroxamic acid.Twentythree grams of2-ethoxy-4-nitrobenzoyl chloride, 7 grams of hydroxylamine hydrochlorideand 12 grams of anhydrous sodium carbonate are suspended in 300 ml. ofdiethyl ether and the mixture stirred vigorously. Tnere is then addeddropwise about 20 ml. of water and the stirring continued for anadditional three hours. The reaction mixture is then concentrated toremove the solvent, and the residue extracted with hot methanol. Themethanol is concentrated and then allowed cool. The desired 2-ethoxy-4-nitrobenzohydroxamic acid crystallizes from the methanol and isrecovered by filtration.

By substituting for the hydroxylamine hydrochloride, an equivalentamount of O-methylhydroxylamine hydrochloride, 0 benzylhydroxylamine, Nmethylhydroxylamine hydrochloride or N,O dimethylhydroxylaminehydrochloride in the above procedure, there is obtained, respectively,O-methyl-2-ethoxy-4-nitrobenzohydroxamic acid,O-benzyl-Z-ethoxy-4-nitrobenzohydroxamic acid,N-methyl-2-ethoxy-4-nitrobenzohydroxamic acid or N,O-dimethyl-2-ethoxy-4-nitrobenzohydroxamic acid.

EXAMPLE 2 2-ethoxy-4-aminobenzohydroxamic acid To a solution of 5 gramsof 2-ethoxy-4-nitrobenzohydroxamic acid in absolute ethanol, there isadded one gram of a 5% palladium on carbon catalyst and the mixture istreated with hydrogen at 50 p.s.i. until the theoretical amount ofhydrogen has reacted. The mixture is then filtered and concentrated toyield the desired 2-ethoxy-4-aminobenzohydroxamic acid.

EXAMPLE 3 2-ethylmercapto-4-nitrobenzohydroxamic acid Following theprocedure of Example 1, but substituting an equivalent amount of2-ethylmercapto-4-nitrobenzoic acid for the 2-ethoxy-4-nitrobenzoicacid, there is obtained the desired2-ethylmercapto-4-nitrobenzohydroxamic acid.

EXAMPLE 4 2-methoxy-4-butylaminobenzohydroxamic acid To a solution of56.3 grams of potassium hydroxide in 140 ml. of methanol there is addeda solution of 46.7 grams of hydroxylamine hydrochloride in 240 ml. ofmethanol at -40". The mixture is cooled to 5 for ten minutes and thereis then added 70 grams of methyl 2-methoxy-4-butylaminobenzoate and themixture filtered immediately. The filtrate is allowed to stand threedays at room temperature in an atmosphere of nitrogen. The reactionmixture is then concentrated at 30 under reduced pressure. The residueis dissolved in a small amount of water, filtered and carefullyneutralized. The precipitated 2-methoxy-4-butylaminobenzohydroxamic acidis purified by crystallization from aqueous methanol.

EXAMPLE 5 2-allyloxy-4-diethylaminobenzohydroxamic acid (a) Methyl 2allyloxy 4 diethylamin0benz0ate. To a solution of 2.3 grams of sodiumdissolved in 300 ml. of methanol there is added 22 grams of methyl-4-diethylaminosalicylate. To this mixture there is then added withvigorous stirring a solution of 12 grams of allyl bromide in ml. ofmethanol. The reaction mixture is stirred vigorously and then warmedgently to complete the reaction. The methanol is removed by distillationand the residue treated with 200 ml. of ether. The sodium bromide isfiltered off and the filtrate concentrated to yield the desired methyl 2allyloxy 4 diethylaminobenzoate.

(b) 2 allyloxy 4 diethylaminobenzohydroxamic acid.Following theprocedure of Example 4, but substituting the methyl 2 allyloxy 4diethylaminobenzoate for an equivalent amount of methyl 2 methoxy- 4butylaminobenzoate, there is obtained the desired 2-allyloxy4-diethylaminobenzohydroxamic acid.

EXAMPLE 6 A conventional basal ration having the following ingredientsis prepared: meat and bone scrap, fish meal, vitamin Bpoultry-by-product meal, dehulled soybean oil meal, dehydrated alfalfameal, corn gluten meal, pulverized oats, ground barley, corn meal, wheatmiddlings, dried grain and whey fermentation solubles, methioninehydroxy analogue calcium, riboflavin, calcium pantothenate, cholinechloride, niacin, animal fat, menadione sodium bisulfite, vitamin Esupplement, butylated hydroxytoluene, vitamin A palmitate, dactivatedanimal sterol, calcium carbonate, defluorinated phosphate, salt, calciumiodate, manganese oxide, zinc oxide, cobalt hydroxide, cobalt carbonate.

A feed composition is prepared by adding 2 ethoxy- 4nitrobenzohydroxamic acid to the basal ration in an amount constituting0.03% by weight of the final mixture. The ingredients are thoroughlyadmixed to provide the ration which is fed to young chicks about 3 weeksold.

EXAMPLE 7 A chick feed is prepared as in Example 6 but substituting0.04% by weight of 2 ethylmercapto 4 nitrobenzohydroxamic acid.

EXAMPLE 8 II I IN-Q-C-N-OR wherein R is hydrogen, R is hydrogen or loweralkyl, R is lower alkyl or lower alkenyl, R is nitro, amino, loweralkylamino or di-lower alkylamino and A is oxygen or sulfur.

2. A compound as in claim 1 wherein R and R each is hydrogen, R is loweralkyl, R is nitro and A is oxygen.

3. A compound as in claim 2 wherein the lower alkyl group is ethyl.

4. A compound as in claim 1 wherein R is hydrogen, R and R each is loweralkyl, R is nitro and A is y n.

5. A compound as in claim 1 wherein R and R each is hydrogen, R is loweralkyl, R is amino and A is oxygen.

6. A compound as in claim 1 wherein R and R each is hydrogen, R is loweralkyl, R is nitro and A is sulfur.

7. A compound as in claim 1 wherein R and R each 2 3lasniyziricggggglgln is lower alkyl, R is lower alkylammo FOREIGNPATENTS 8. A compound as in claim 1 wherein R and R each 744,307 2/1956Grat Britain. is hydrogen, R is lower alkenyl, R is di-lower alkyl-375,178 6/1962 p amino and A is oxygen.

5 BERNARD HELFIN, Primary Examiner References Cited UNITED STATESPATENTS 2,279,560 4/1942 Dietrich. 3,226,387 12/1965 Newbold et a1. 199-4; 260453, 544; 424 298,315

I. E. EVANS, Assistant Examiner

